Sexual transmission is the most common route of HIV infection. Women account for nearly half of those infected worldwide and more than 70% in sub-Saharan Africa (UNAIDS report 2006). Prevention strategies employing different approaches are needed to reduce the probability of transmission. Epidemiological and clinical studies strongly indicate that sexually transmitted infections (STIs) increase the likelihood of HIV transmission. Although the contribution of STIs to the increase in HIV transmission is likely to be multifaceted, understanding how STIs enhance HIV infection is vital to the development of new strategies to reduce the spread of HIV. [unreadable] [unreadable] Mammalian defensins are antimicrobial peptides important to innate host defense and are thought to play a role in mucosal immunity. Human defensins 5 and 6 (HD5 and HD6) are constitutively expressed in intestinal Paneth cells and HD5 is found in the epithelium of the vagina and ectocervix. Induction of HD5 has been recently found in the male urethra during C. trachomatis and N. gonorrhoeae infection, supporting a role in STIs. However, a more complex picture emerged in our preliminary studies indicating that HD5 and HD6 significantly enhance HIV infection at the step of viral entry. Using cervicovaginal tissue culture systems, we found that, for the first time, HD5 and HD6 were induced in response to gonococcal infection. Therefore, we hypothesize STIs may contribute to increased HIV transmission in these individuals due the high level induction of HD5 and HD6 in the genital mucosa. [unreadable] [unreadable] The goal of this proposal is to begin to dissect the mechanism of HD5 and HD6-mediated enhancement of HIV-1 entry and to explore their putative role in facilitating transmission in conjunction with STIs employing our novel in vitro infection system. Mechanistic studies will define the specific step in viral infection that is enhanced by HD5 and HD6 will define if the enhancement is through direct effects on the virus and/or the target cell and will start to define components of viral gp120 that might be critical to this enhancement. This study will provide further insight into the complex function of defensins in HIV-1 pathogenesis and transmission, and investigate the interaction between this host response and candidate topical microbicides. A longer term outcome could be the development of novel prevention strategies. [unreadable] [unreadable] [unreadable] [unreadable]